Identification of a novel hypomorphic variant in CYBB underlying an adult presentation of X-linked recessive Mendelian susceptibility to mycobacterial disease

Deleterious mutations in the CYBB gene encoding NOX2 typically cause X-linked recessive chronic granulomatous disease (XR-CGD) by affecting NADPH oxidase-dependent respiratory burst in phagocytes. However, two missense variants (T178P, Q231P) were previously shown to cause isolated Mendelian susceptibility to mycobacterial disease (MSMD) in otherwise healthy males. We describe a novel, private variant in CYBB (c.998C>A, p.S333Y) identified in a male patient with adult-onset disseminated Mycobacterium avium infection. Despite preserved transcript levels, NOX2 protein expression was reduced in the patient's cells. Functionally, an intermediate phenotype was observed, characterized by reduced but not abolished ROS production, with a cell-type specific degree of impairment. This case represents the second report of isolated X-linked recessive MSMD caused by a missense CYBB variant, and the first case presenting in adulthood. Our findings indicate a hypomorphic variant that impairs respiratory burst in a cell type-specific manner, extending previous observations in two kindreds with CYBB-associated MSMD.